Progression to diabetes in relatives of type 1 diabetic patients: mechanisms and mode of onset.

  1. Ele Ferrannini, MD (ferranni{at}ifc.cnr.it)1,
  2. Andrea Mari, PhD2,
  3. Valentina Nofrate, PhD2,
  4. Jay M. Sosenko, MD3,
  5. Jay S. Skyler, MD3 and
  6. for the DPT-1 Study Group
  1. 1 Department of Medicine, University of Pisa School of Medicine, Pisa, Italy
  2. 2 C.N.R. Institute of Biomedical Engineering, Padua, Italy
  3. 3 Division of Endocrinology, University of Miami, USA

Abstract

Objective Relatives of type 1 diabetic patients are at enhanced risk of developing diabetes. We investigated the mode of onset of hyperglycemia and how insulin sensitivity and ß-cell function contribute to the progression to the disease.

Research design and methods In 328 islet-cell-autoantibody-positive, non-diabetic relatives from the observational arms of the Diabetes Prevention Trial-1 Study (age=11 [8] years (median [interquartile range]), sequential OGTTs (2,143 in total) were performed at baseline, every six months, and 2.7 [2.7] years later, when 115 subjects became diabetic. ß-cell glucose sensitivity (slope of the insulin-secretion/plasma glucose dose-response function) and insulin sensitivity were obtained by mathematical modeling of the OGTT glucose/C-peptide responses.

Results In progressors, baseline insulin sensitivity, fasting insulin secretion, and total postglucose insulin output were similar to those of non-progressors, whereas ß-cell glucose sensitivity was impaired (48 [36] vs 87 [67] pmol.min−1.m−2.mM−1, p<0.0001), and predicted incident diabetes (p<0.0001) independently of sex, age, BMI, and clinical risk. In progressors, 2-hour glucose levels changed little until 0.78 years before diagnosis, when they started to rise rapidly (∼13 mmol.l−1.year−1); glucose sensitivity began to decline significantly (p<0.0001) earlier (1.45 years before diagnosis) than the plasma glucose surge. During this anticipation phase, both insulin secretion and insulin sensitivity were essentially stable.

Conclusions In high-risk relatives, ß-cell glucose sensitivity is impaired and is a strong predictor of diabetes progression. The time trajectories of plasma glucose are frequently biphasic, a slow linear increase being followed by a rapid surge, and are anticipated by a further deterioration of ß-cell glucose sensitivity.

Footnotes

    • Received September 16, 2009.
    • Accepted December 11, 2009.

This Article

  1. Diabetes
  1. Online-Only Appendix
  2. All Versions of this Article:
    1. db09-1378v1
    2. 59/3/679 most recent